Nature Genetics33, 459 - 461 (2003)
Published online: 17 March 2003; | doi:10.1038/ng1130
Polyalanine expansion and frameshift mutations of the paired-like homeobox gene PHOX2B in congenital central hypoventilation syndrome
Jeanne Amiel1, Béatrice Laudier1, Tania Attié-Bitach1, Ha Trang2, Loïc de Pontual1, Blanca Gener3, Delphine Trochet1, Heather Etchevers1, Pierre Ray1, Michel Simonneau2, Michel Vekemans1, Arnold Munnich1, Claude Gaultier2
& Stanislas Lyonnet1
1
Unité de Recherches sur les Handicaps Génétiques de l'Enfant INSERM U-393, et Département de Génétique, Hôpital Necker-Enfants Malades, 149, rue de Sèvres, 75743 Paris Cedex 15, France.
2
Service de Physiologie CIC INSERM 9202, et Equipe INSERM E9935, Hôpital Robert Debré, Paris, France.
3
Clinica Materno-Infantil, Hospital de Cruces, 48903 Barakaldo, Spain.
Correspondence should be addressed to Jeanne Amiel amiel@necker.fr
Congenital central hypoventilation syndrome (CCHS or Ondine's curse; OMIM 209880) is a life-threatening disorder involving an impaired ventilatory response to hypercarbia and hypoxemia. This core phenotype is associated with lower-penetrance anomalies of the autonomic nervous system (ANS) including Hirschsprung disease and tumors of neural-crest derivatives such as ganglioneuromas and neuroblastomas. In mice, the development of ANS reflex circuits is dependent on the paired-like homeobox gene Phox2b. Thus, we regarded its human ortholog, PHOX2B, as a candidate gene in CCHS. We found heterozygous de novo mutations in PHOX2B in 18 of 29 individuals with CCHS. Most mutations consisted of 5−9 alanine expansions within a 20-residue polyalanine tract probably resulting from non-homologous recombination. We show that PHOX2B is expressed in both the central and the peripheral ANS during human embryonic development. Our data support an essential role of PHOX2B in the normal patterning of the autonomous ventilation system and, more generally, of the ANS in humans.
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